Rhodium-Catalyzed Carbonylative Coupling of Alkyl Halides with Phenols under Low CO Pressure

Article abstract of DOI:10.1021/acscatal.0c00933

A rhodium-catalyzed carbonylative transformation of alkyl halides under low pressure of CO has been developed. This robust catalyst system allows using phenols as the carbonylative coupling partner and, meanwhile, exhibits high functional group tolerance and good chemoselectivity. Substrates even with a large steric hindrance group or multiple reaction sites can be selectively converted into the desired products in good to excellent yields. A gram-scale experiment was performed and delivered an almost quantitative amount of the product. Control experiments were performed as well, and a possible reaction mechanism is proposed.

Full text of DOI:10.1021/acscatal.0c00933

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Letter
Rhodium-Catalyzed Carbonylative Coupling of
Alkyl Halides with Phenols under Low CO Pressure
Han-Jun Ai, Hai Wang, Chong-Liang Li, and Xiao-Feng Wu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00933 • Publication Date (Web): 13 Apr 2020
Downloaded from pubs.acs.org on April 13, 2020
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ACS Catalysis
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Rhodium-Catalyzed Carbonylative Coupling of Alkyl Halides with
Phenols under Low CO Pressure
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Han-Jun Ai, Hai Wang, Chong-Liang Li, and Xiao-Feng Wu*
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
ABSTRACT: A rhodium-catalyzed carbonylative transformation of alkyl halides under low pressure of CO has been
developed. This robust catalyst system allows using phenols as the carbonylative coupling partner, meanwhile,
exhibits high functional group tolerance and good chemoselectivity. Substrates even with large steric hindrance
group or multiple reaction sites can be selectively converted into the desired products in good to excellent yields. A
gram scale experiment was performed and delivered almost quantitative amount of the product. Control experiments
were performed as well and a possible reaction mechanism is proposed.
KEYWORD: Rhodium Catalyst; Carbonylation; Phenol; Ester; Carbonylative Coupling; Alkyl Halides
Supporting Information Placeholder
Esters are common structural motifs in natural products,
pharmaceuticals, agricultural chemicals and materials.1 Due to
the accepted importance, numerous synthetic approaches
have been developed for their preparation during the past
decades. Compared with the traditional methods by
esterification of alcohols and phenols with activated
carboxylic acids2 or related derivatives3, in which the carbonyl
group is pre-incorporated, transition-metal-catalyzed
carbonylation has attracted much interest due to its
modularity and direct employing carbon monoxide (CO) as a
cheap and abundant C1 source and without generating
possible by-products from Friedel-Crafts acylation reactions.4
general and practical method for carbonylative coupling of
alkyl halides and phenols (Scheme 1c). This rhodium-
catalyzed transformation enables the efficient synthesis of
diverse esters under low CO pressure with high functional
group tolerance and good chemoselectivity.
Scheme 1. Synthesis of Esters by Carbonylation
Reactions.
(a) General concept of carbonylative esterification of alkyl halides
O
O
CO
ROH
M
Alkyl
X
Alkyl MX
Alkyl
MX
Alkyl
OR
The direct carbonylative synthesis of esters would thus
provide an attractive strategy. Carbonylative transformation
of aryl halides has been extensively studied, however, the
carbonylative transformation of alkyl halides faces more
challenges. On one hand, the difficulty on oxidative addition of
C(sp3)–X bonds to low-valent metal complexes is increasing in
the presence of CO, due to its coordination with metal and
subsequently decreasing the electron density of the metal
center (CO deactivating coordination).5 On the other hand, the
fast β-hydride elimination of the alkyl-metal intermediates is
prone to occur (Scheme 1a).6 To overcome these challenges,
high CO pressure and/or intense Xe lamp/light irradiation or
excess peroxides are usually required (Scheme 1b).7 To date,
prone to -H elimination
MX
O
CO
Alkyl
MX
+
Alkyl
high pressure of CO required
(b) Previous work and limitations
R1 = alkyl, benzyl
metal, peroxides or hv
R1 = aryl
O
Alkylphenol
esters
Alkyl X + R1
R1
OH
CO (1-80 bar)
Alkyl
O
R
(c) This approach: phenols as carbonylative coupling partner with alkyl halides
HO
O
Rh cat.
CO
1 bar
Alkyl
X
+
+
Alkyl
O
only
a
few procedures been reported capable of
R
77 examples
average yield  89%
X = I, Br
alkoxycarbonylation under low CO pressure and with
aliphatic alcohols as the reaction partner.8 Moreover, to date,
there is only one example on carbonylation of (3-
iodopropyl)benzene with phenol as the coupling partner was
reported, which produced 38% yield of phenyl 4-
phenylbutanoate under 400 bar pressure with Xe lamp.9 This
situation can mainly be explained from two aspects: (i) in the
presence of base, haloalkanes and phenols are prone to occur
nucleophilic substitution reaction to give ethers; (ii)
carbonylation of haloalkanes usually proceed via free radical
intermediates, which trend to be quenched by phenols.
In our previous studies, phenols failed to be esterified by
carbonylation of alkyl halides by using Pd, Cu, Ni or Mn
catalyst systems.10 We suspect that those metal complexes are
difficult to form R(CO)-M-X intermediate before alkyl halides
reacts with phenols. Inspired by Monsanto process, which
shows that rhodium complex can insert into the Me(sp3)–I
bond relatively easy, we set our sights on rhodium catalysis.
However, the reaction rate of Monsanto process
(carbonylation of the alcohols) sharply decreased when alkyl
carbon chain increasing (MeOH > EtOH > n-PrOH with relative
Herein, attracted by these challenges, and based on our
longstanding interest in carbonylation reactions, we report a
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Page 2 of 6
rates at 170 °C of 21:1:0.47).11 Inspired by these information,
we become interested to explore rhodium catalyst for
carbonylation of alkyl halides with phenol nucleophiles.
demonstrated.12b,12c Here the added NaBr or NaCl might
become NaI with released iodide from substrate and then
deliver similar results as NaI. Remarkably, by simply
extending the reaction time, good yield can still be obtained
with decreased loading of catalyst and ligand.
1
2
3
4
5
6
With the optimized reaction conditions in hand, we then
explored the scope of phenols (Table 2). At the first stage, we
used a variety of phenols containing different functional
groups (Table 2A). Good to excellent yields of the target
products can be produced from substrates substituted with
electron-donating group or electron-withdrawing group (3 –
23). Meanwhile, a variety of substituents, such as halogens
(16, 17, 18), -COOMe (19), -Ac (20), -CHO (21), -CN (22) and -
NO2 (23), were tolerated, gave the corresponding esters in
high yields. Notably, gram synthesis was also successful and
almost quantitative yield of 8 was obtained even we scaled up
the reaction ten-folds, thus providing potential opportunity
for applications in large scale production. Subsequently, to
test the effect of steric hindrance on the reaction, phenols with
different groups substituted at ortho position were used
(Table 2B). Methyl, isopropyl or phenyl had no effect to the
reaction outcome and provided the corresponding products
24 – 26 and 29 in excellent yields, respectively. As the steric
hindrance was further increasing, remarkably, 27 and 28 can
still be obtained in over 80% yield, and ortho-disubstituted
phenols such as 2,6-dimethyl-phenol or 2,6-diphenyl-phenol
were also performed well, affording 30 and 31 in excellent
yields. Remarkably, phenols which in the ortho position have
a strong coordination group such as -CHO, -allyl, -CN and-Ac
also successfully delivered the desired products 32 – 37 in
good to excellent yields. Next, we investigated the selectivity
of the reaction by using phenols with multiple reaction sites
(Table 2C). For example, diphenols were successful converted
into the corresponding diesters 40 – 42 in excellent yields.
And when we used phenols contain -NH motifs such as 2-
hydroxycarbazole, 5-hydroxyindole and 4-acetamidophenol
(paracetamol), without the need to protect the amines, the
target products 43 – 45 were selectively obtained. Primary
amines were not compatible with the reaction, might due to
the strong nucleophilicity. When we placed -CH2OH group in
the para position of phenol, we were surprised to find that the
carbonylation only occurred at the phenolic hydroxyl group
and provided 46 in 80% yield. This might due to the fact that
phenols can be easily deprotonated under basic conditions to
give ArONa which is a better nucleophile than alcohols and
even amine. In addition, iodide-substituted phenols, such as p-
iodophenol and o-iodophenol, were successfully converted to
iodide-substituted phenol esters (47 and 48), offering
opportunities for further structure modification. The utility of
this carbonylation reaction can also be demonstrated by the
modification of bioactive molecules. As shown in Table 2D, the
compound, Furaneol, which commonly used for baking bread,
proceeded with 2 successfully (49). Antioxidants, such as
Sesamol and Vitamin E, were also applicable to the reaction
(50, 52). And drugs of great value, Estrone and Ezetimibe,
delivered carbonylation products 51 and 53 respectively. In
particular, the selective carbonylation of Ezetimibe with the
alkyl hydroxyl group intact provided a convenient synthetic
method for modification of bioactive molecules without the
need for protection–deprotection procedure, thus providing
potential opportunity for applications in medicinal chemistry.
Table 1. Representative Results for the Optimization of
Rh-Catalyzed Carbonylative Coupling of 1 with 2.a
7
8
9
RhCl3 (5 mol%)
O
OH
Ligand
CO
(1 bar)
I
+
+
O
Na2CO3 (1 eq.)
dioxane
120 °C, 24 h
2
1
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
1
Ligand (mol%)
DPPP (5)
M (mol/L)
Yieldb (%)
7
0.2
0.25
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
2
DPPP (5)
10
3
DPPP (5)
12
4
DPPP (10)
DPPP (12.5)
DPPP (15)
DPPP (20)
DPPE (15)
DPPB (15)
PPh3 (30)
PCy3 (30)
44
5
65
6
80
7
75
8
41
9
41
10
11
12
13
29
17
DPPP (15)
DPPP (7.5)
98c
83c,d
aRhCl3 (5 mol%), ligand, CO (1 bar), N2 (5 bar), Na2CO3 (1
equiv), phenol (0.2 mmol), iodobutane (1.6 equiv), dioxane,
120 C, 24 h. Determined by GC with hexadecane as internal
standard. With NaBr, NaCl or NaI (10 mol%) as additive. 2.5
mol% of RhCl3 was used and the reaction was conducted for
45 h.
o
b
c
d
Our
attempting
started
with
Rh/DPPP
(1,3-
bis(diphenylphosphino)propane) catalyst system employing
phenol and iodobutane as the starting materials. To our
delight, 7% yield of alkylphenol ester 3 was detected when
Na2CO3 was used as the base and dioxane as the solvent
(Table 1, entry 1). The yield can be improved by increasing
the reaction concentration (Table 1, entries 1-3). To our
surprise, the yield improved significantly to 80% by
increasing the amount of ligand (Table 1, entries 4-7). The
catalytic system gave the highest efficiency when the initial
ratio of Rh/P was 1/6. The requirement of the presence of
excess phosphine ligand might due to the reason that
phosphine ligand had to compete with CO to coordinate with
rhodium in this gas atmosphere. The Rh/DPPP catalyst system
was crucial to this transformation. When we increased or
decreased the bite angle of the bidentate ligand or used a
monodentate ligand, the yield dropped dramatically (Table 1,
entries 8-11; for more details see supporting information).
Finally, the most economical combination, RhCl3 and DPPP,
gave the highest yield (Table 1, entry 6). To further improve
the catalytic activity of the Rh complexes for this
transformation, various additives were tested (for more
details see supporting information).12 Almost quantitative
yield of the product was obtained when 10 mol% of NaBr,
NaCl or NaI was added (Table 1, entry 12). The using of NaI as
additive can promote carbonylative transformation was
2
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ACS Catalysis
Table 2. Scope of Phenols.a
1
RhCl3 (5 mol%), DPPP (15 mol%)
NaBr (10 mol%), Na2CO3 (1 eq.)
dioxane (0.4 M), 120 °C, 24 h
nBu
OH
O
2
3
CO
1 bar
nBu
+
+
R
I
R
O
4
5
6
7
A. Phenols with EDG or EWG
nBu
4
(R = Me), 97%
O
nBu
O
nBu
O
O
nBu
O
nBu
5
6
7
8
(R = Et), 99%
O
t
O
O
Me
Ph
O
(R = Bu), 93%
O
R
(R = OMe), 99%
(R = Ph), 99%; 99%
Ph
8
Me
10, 99%
e
Me
9
3,
, 99%
96%
11
, 99%
b
9
O
O
O
O
nBu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
nBu
O
nBu
O
19
20
21
22
23
(R = COOMe), 99%
nBu
O
nBu
O
e
(R = Ac), 93%
R
16
O
O
e
e
N
(R = CHO), 97%
(R = F), 99%
e
13
, 95%
12
(R = CN), 97%
(R = NO2), 75%
, 99%
17
18
(R = Cl), 99%
(R = Br), 99%
14
, 99%
15
, 97%
B. Phenols with steric hindrance
nBu
nBu
O
nBu
O
nBu
O
nBu
O
O
O
O
Me
tBu
e
O
O
O
tBu
iPr
Me
Me
Me
e
28
27
, 80%
25
, 87%
, 99%
24
, 99%
26
, 99%
Me
Ph
CHO
COPh
O
nBu
nBu
O
nBu
nBu
O
nBu
O
O
O
Ph
O
O
O
e
O
Me
Ph
29
, 99%
e
32
, 94%
31
33
Br
, 76%
30
, 91%
, 99%
CHO
Allyl
CN
nBu
Ac
F
F
O
nBu
O
nBu
nBu
nBu
O
nBu
O
O
O
O
Br
O
O
O
O
O
Me
F
Br
e
38
e
, 96%
c
e
37
, 71%
36
35
, 77%
39
, 67%
, 99%
34
, 75%
C. Phenols with multiple reaction sites
O
O
O
O
nBu
H
N
O
O
nBu
nBu
O
nBu
nBu
O
O
nBu
O
nBu
O
O
O
d
41
, 97%
nBu
O
43
, 82%
d,e
d
40
, 90%
42
, 99%
nBu
nBu
O
I
nBu
O
nBu
O
O
O
O
HO
O
O
O
O
e
O
e
N
H
N
H
Me
I
47
, 61%
e
48
, 96%
44
, 99%
45
, 99%
46
, 80%
D. Modification of bioactive molecules
O
Me
Me
F
O
O
F
O
O
nBu
Furaneol
O
nBu
N
H
H
O
O
e
49
O
, 76% , from
,
OH
spices of flavor and perfume industry
H
nBu
O
3
3
3
O
O
nBu
O
O
O
53
Ezetimibe, nBu
e
52
Vitamin E
,
51
Estrone
, 92% from
, 96% from
estrogen drugs
,
, 61% from
O
O
antioxidant
antihyperlipidemic agent
50
Sesamol
,
, 99% from
antioxidant
aRhCl3 (5 mol%), DPPP (15 mol%), CO (1 bar), N2 (5 bar), Na2CO3 (1 equiv), phenols (0.5 mmol), iodobutane (0.8 mmol), NaBr (10
mol%), dioxane (1.25 mL), 120 oC, 24 h. The reaction was performed on a 0.5 mmol scale with isolated yield. bGram-scale synthesis,
obtained 1.27g of 8 on a 5 mmol scale. cThe reaction was performed on a 0.2 mmol scale. d0.25 mmol phenol was used. ewith 95%
purity, measured by 1H NMR.
3
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Table 3. Scope of Alkyl Halides.a
1
RhCl3 (5 mol%), DPPP (15 mol%)
additive:
OH
CO
2
3
4
5
6
7
8
R
O
additive, Na2CO3 (1 eq.)
dioxane (0.4 M), 120 °C, 24 h
+
+
RX
X=I
X=Br
NaI (80 mol%)
1 bar
or
O
NaBr (10 mol%)
X = I
Ph
O
Me
O
Ph
nMe
55
56
57
O
O
, (n = 1), 99%
, (n = 7), 99%
, (n = 17), 99%
O
Ph
O
O
Ph
O
O
O
58
,
96%b,d
d
54
, 97%
b
60
, 46%
59
, 78%
9
O
5 I
O
O
O
O
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF3
O
O
O
O
O
b
d
I
62
61
, 99%
, 99%
b
63
, 38%
64
, 71%
X = Br
nBu
O
O
5
O
O
O
Ph
O
Me
Me
O
Me
O
O
O
O
O
d
d
d
66
65
, 99%
, 99%
Me
Me
58
, 81%
3
67
, 88%
, 99%
15% without NaI
68
, 80%
n
I
O
O
N
O
Me
O
O
Me
CN
O
O
O
O
3
O
O
O
d
d
d
72
73
74
, (n = 1), 70%
, (n = 2), 91%
, (n = 3), 87%
c,d
75
, 69%
O
O
d
69
, 75%
71
, 84%
70,
80%
Ph
Z:E=1:2.3
d
76
, 75%
X = OTs; NaI (80 mol%)
X = OMs; NaI (80 mol%)
nBu
O
nBu
O
O
3
, 54%
3
, 60%
O
58
, 49%
O
O
aRhCl3 (5 mol%), DPPP (15 mol%), CO (1 bar), N2 (5 bar), Na2CO3 (1 equiv), phenols (0.5 mmol), alkyl halides (0.8 mmol), NaBr (10
mol%) or NaI (80 mol%), dioxane (1.25 mL), 120 C, 24 h. bThe reaction was performed on a 0.2 mmol scale. trans-1-Bromo-2-
o
c
butene (85% purity) was used. dwith 95% purity, measured by 1H NMR.
Scheme 2. Mechanistic Studies.
Next, the scope with respect to different alkyl iodides or
A
O
Me
bromides was examined. (Table 3). Both can be successful
converted to the corresponding esters when different
additives were used. By decreasing or increasing the carbon
chain of the alkyl halides, good yields of the desired products
can still be obtained (54 – 59, 66 - 69). In addition, benzyl
bromide could also be transformed to the target product 65
with excellent yield. However, secondary haloalkane gave
moderate yield (60). Good functional group compatibility
was observed with the tolerance of trifluoromethyl (61),
thioether (62), ester (64), imide (70), cyanide (71) and
olefin (72 - 75) groups. In particular, the carbonylation was
selectively carried out on the site of alkyl iodide, while the
aryl iodide was retained (64, 76). Notably, when
bromobutane was tested without NaI, only 15% yield of 3
was obtained. The addition of NaI in the cases of alkyl
bromides is for the in-situ alkyl iodides formation via
Finkelstein reaction and then ready for the designed
carbonylation reaction. Finally, alkyl tosylates and mesylate
were tested with phenol under the conditions for alkyl
bromides as well, the target products can be successfully
produced (3, 58).
O
Me
standard conditions
O
78
, not observed
77
nBu
B
1
O
N
O
nBu
Me
Me
Me
Me
standard conditions
+
+
2
+
with TEMPO (2 equiv)
O
3
, trace
79
, detected by GC-MS
C
1
O
O
O
standard
I
+
O
conditions
80
73
, 74%
O
81
, 15%
I
D
1
Me
Me
standard
conditions
Me
Me
nBu
+
O
Me
+
and
O
O
I
3
, 81%
82
, not observed
tBu
E
nBu
OH
O
standard conditions
standard conditions
1
+
2
+
O
tBu
, (2 equiv)
3
, 99%
83
F
Here it is also important to mention that a small amount
of ether via SN2 alkylation can be detected during the studies
as well.13 Additionally, ester byproduct (RCO2R) which
produced by carbonylative homocoupling of the alkyl halide
can also be obtained which is also difficult to separate from
O
O
nBu
Ph
1
+
2
+
Ph
, (2 equiv)
84
3
, 99%
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ACS Catalysis
our target esters. In the reaction, Na2CO3 been transformed
alkylphenol ester were efficiently prepared with excellent
selectivity. Secondary amine, C(sp3)-OH and C(sp2)–I can be
retained under the conditions thus offering opportunities for
further structure modifications. The possibility on gram
scale synthesis providing potential opportunity for
applications in large scale production.
1
2
3
4
5
6
7
8
into NaHCO3 which will give Na2CO3, H2O and CO2 after
thermal disproportionation. The produced H2O will react
with RX to give ROH which then produce RCO2R after
carbonylation reaction.13
To gain more mechanistic insight into the reaction
pathway, several control experiments were conducted
(Scheme 2). Under the standard conditions, anisole couldn’t
be converted into the ester 78 (Scheme 2A), which indicated
the carbonylative coupling did not undergo the process of
ether. Subsequently, the addition of TEMPO (a radical
scavenger, 2 equiv) to the reaction mixture and the target
reaction was inhibited together with the detection of 79 in
GC-MS (Scheme 2B). Furthermore, in the reaction of 1 and
80 under the standard conditions, the ring-opening
expansion product 73 was obtained in 74% yield and
together with 15% yield of product 81 (Scheme 2C).
However, due to the existing of other pathways for
alkylation of TEMPO and rhodium-catalyzed two-electron
rearrangement of cyclopropyl group,14 we suggest that free
radical intermediates might be involved in this
carbonylation process. Subsequently, the competition
reaction showed that primary alkyl halide was much more
reactive than secondary alkyl halide under the same reaction
environment (Scheme 2D). In addition, whether we added
2,6-di-tert-butylphenol 83 (a radical inhibitor) (Scheme 2E)
or α-phenyl styrene 84 (a radical scavenger) (Scheme 2F),
the desired product 3 can still be obtained in excellent yields.
AUTHOR INFORMATION
Corresponding Author
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* E-mail: xiao-feng.wu@catalysis.de
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Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
General comments, general procedures, analytic data and
NMR spectra for products (PDF)
Based on the above results and previous reports,11
a
ACKNOWLEDGMENT
plausible mechanism is proposed (Scheme 3). The reaction
starts with oxidative addition of alkyl halides to rhodium(I)
species A which might also be the rate determine step. The
resulted [AlkylRhIIILXn+1] B intermediate reacts with CO
subsequently to provide the alkylacyl rhodium(III) complex
[AlkylCO-RhIIILX n+1] C. In the presence of base, phenol
nucleophilic attacks C and gives D. Finally, the rhodium
complex D undergoes reductive elimination to produce the
final ester product and meanwhile release Rh(I) complex for
the next catalytic cycle.
The authors thank the Chinese Scholarship Council (CSC) for
financial support. We also thank the analytical team of
LIKAT for their excellent analytic support.
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RhI
[
(L)Xn]
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Alkyl
A
Alkyl
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Ar
AlkylCO RhIII
[
-
LXn]
AlkylRhIII
[
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CO
HX
base
ArOH
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[
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]
C
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catalyzed carbonylation of alkyl halides under low CO
pressure. Under the standard conditions, various
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R
a)
b)
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NaHCO3
NaX
Na2CO3 + CO2 + H2O
H2O
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[Rh], CO
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R
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Graphic abstract:
Alkyl
O
Rh cat.
CO (1 bar)
Aryl
Alkyl
X
OH
+
Aryl
O
X = I, Br, OTs, OMs
80 examples
average yield  89%
Phenols as carbonylative coupling partner
Excellent selectivity
Excellent steric tolerance
Excellent functional group tolerance
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